Csf Diagnostic in Vitro Method for Diagnosis of Dementias and Neuroinflammatory Diseases

ABSTRACT

CSF diagnostic in vitro method for the diagnosis of dementias and neuroinflammatory diseases, in which a determination of the procalcitonin immunoreactivity (PCT immunoreactivity) is carried out in a sample of cerebrospinal fluid (CSF) of a patient who is suffering from a dementia or neuroinflammatory disease or is suspected of suffering from such a disease. Conclusions about the presence, the course, the severity or the success of a treatment of the dementia or neuroinflammatory disease are drawn from a measured PCT immunoreactivity which is above a threshold value typical for healthy individuals.

The present invention relates to a novel CSF diagnostic in vitro methodfor diagnosis of dementias and neuroinflammatory diseases.

In the context of the present invention, the term “diagnosis” is used asa general term for medical determinations which, depending on theclinical state of the patient for whom the determination is carried out,may be based on different problems and which serve in particular fordetection and early detection, determination of severity and monitoring,including monitoring during the treatment, and prognosis of the futurecourse of the disease.

The method according to the invention is a CSF diagnostic in vitromethod. A CSF diagnostic method is understood as meaning a method whichis usually carried out in the course of the diagnosis of neurologicaldiseases and in which the determination of a property of the so-calledcerebrospinal fluid (CSF) which is informative for diagnostic purposesis effected. In the case of the present invention, the specific propertyis the immunodiagnostically determinable content of a biomolecule in theCSF.

The diseases which are diagnosed according to the present invention arein particular presenile dementias, as will be discussed in more detailin the present Application, and further chronic neuroinflammatorydiseases of non-infectious aetiology.

Dementias are generally defined as diseases for which a common featureis the loss of acquired intellectual capabilities, especially of thememory, and of the normal level of the personality as a consequence ofbrain damage. Dementias are as a rule relatively slowly developingdiseases of chronic character. If dementia phenomena occur before oldage, in middle aged people, they are referred to as presenile dementiasand, on the basis of the symptoms typical of them and pathologicalchanges in the brain, a differentiation is made in particular betweenthe following four diseases or groups of diseases:

Alzheimer's dementia (AD) (Alzheimer's disease) is the most frequentneurodegenerative dementia and accounts for ⅔ of all cases of dementia.AD is distinguished by three important pathological features: theformation of amyloid plaques and neurofibrillar bundles and the loss ofnerve cells (for an overview, cf. 24; references in the description inthe form of numbers refer to the list of references following thedescription). Amyloid plaques consist of extraneuronal aggregates ofamyloid-β-protein, while the neurofibril bundles contain mainlytau-protein and neurofilaments. It is presumed that the plaque andneurofibril formation is the cause of the death of nerve cells.

The most important symptoms of AD are increasing dysfunctions of memoryand intellect with relatively persistent emotional responsiveness, thesesymptoms being accompanied by further less specific disturbances whichmake it difficult to differentiate AD from other forms of dementia.

Dementia with Lewy bodies (DLB) is the second most frequent cause of adementia after Alzheimer's dementia (11; 18). Neuropathologically, DLBis characterized by the occurrence of so-called Lewy bodies in the brainstem and in the cortex. These Lewy bodies consist predominantly ofaggregates of the presynaptic protein (α-synuclein) and ubiquitin. Lewybody pathology can be associated to different extents withneuropathological changes typical of Alzheimer's and Parkinson'sdisease. Thus, in DLB too, the formation of β-amyloid and senile plaquesoccurs, but not neurofibril bundles (for an overview, cf. 6) . Lewybodies are also present in the brain of patients with Parkinson'sdisease, even if in a different distribution (for an overview cf. 19).

Key symptoms of DLB are a progressive cognitive disturbance, episodes ofconfusion with fluctuating attention and consciousness, Parkinsonism,frequent falls and syncopes (brief, paroxysmal unconsciousness) (17).The sensitivity and specificity of the diagnostic criteria (17) showhigh specificity throughout but a very low sensitivity in some cases.This means that DLB is frequently not diagnosed in clinical routine. Inparticular the differentiation from Alzheimer's disease must be furtherimproved.

Frontotemporal dementia (FTD) is also referred to as Pick's disease andaccounts for about 20% of presenile dementias. FTD is genetic in somecases and is among the so-called tauopthies, which are distinguished byoverexpression or underexpression of a tau-protein subtype (34) or bythe expression of a mutated tau-protein (23). Neuropathological symptomsare local atrophy of the frontal and/or temporal cortex and of thesubstantia nigra and of the basal ganglia. This results in differentlevels of speech disturbance, a change of personality and behaviouralpeculiarities. Overall, FTD is underdiagnosed with a sensitivity of 93%and a specificity of only 23%, AD being the most frequent misdiagnosis(30).

The term vascular dementia (VAD) covers diseases in which a dementia istriggered owing to disturbed blood flow in the brain. There aredifferent types of VAD, of which multi-infarction dementia (MID) andsubcortical VAD (also referred to as Binswanger's disease) are the mostfrequent forms.

Binswanger's disease is a slowly progressing dementia which ischaracterized pathologically by cerebrovascular lesions in the whitebrain substance. Clinically this results in behavioural peculiarities,such as agitation, irritability, depression and euphoria, and slightmemory disturbance (4).

Multi-infarction dementia arises gradually as a consequence of severalsmall strokes, also referred to as transient ischaemic attacks (TIA),which led to the destruction of brain tissue in the cortex and/orsubcortical areas (9). The strokes may also have remained completelyunnoticed, in which case the dementia is the first noticeableconsequence. In the presence of MID, there is a gradual decrease incognitive capabilities, associated with severe depressions, moodfluctuations and epilepsy.

A diagnosis of dementias is performed nowadays predominantly on thebasis of neuropsychological investigations and the observation of thedevelopment of the disease and its course using exclusion criteria forcertain forms of dementia. In very many cases, these investigations giveambiguous results, which explain the abovementioned numbers for theunderdiagnosed forms of dementia or incorrectly diagnosed cases. Thecerebral changes typical of the disease cannot of course be establisheddirectly in living patients and technical medical investigations ofbrain function by means of, for example, X-ray tomography or MRI arecomplicated and expensive.

There is a need for supplementary methods of investigation which permitdiagnosis of dementia and which facilitate in particular thedifferentiation of different forms of dementia with similar or blurredclinical symptoms, an immunodiagnostic determination of biomarkers of asuitable specificity and sensitivity being particularly desirable.

The present invention provides such a method of investigation in theform of a CSF diagnostic in vitro method for detection and earlydetection, for the determination of severity and for monitoring andprognosis of dementias and neuroinflammatory diseases according to claim1, in which a determination of the procalcitonin immunoreactivity (PCTimmunoreactivity) is carried out in a sample of the cerebrospinal fluid(CSF) of a patient who is suffering from a dementia or neuroinflammatorydisease or is suspected of suffering from such a disease, andconclusions about the presence, the type, the course, the severity orthe success of a treatment of the dementia or neuroinflammatory diseaseare drawn from a measured PCT immunoreactivity, which is above athreshold value typical for healthy control persons.

In particular, the PCT determination in the CSF is effected, asemphasised in claim 2, with the aid of a highly sensitive PCTimmunoassay having a functional assay sensitivity (FAS) of better than100 ng of PCT per 1 (100 ng/l or 100 pg/ml), in particular better than50 ng/l and particularly preferably better than 10 ng/l.

Advantageous developments of the method according to claims 1 and 2 aredescribed in subclaims 3 to 12.

Since the measurements described in more detail below have shown thatthe PCT immunoreactivity in CSF can be measured with high precision andreliability by a highly sensitive immunoassay having a functional assaysensitivity (FAS) which is considerably better than that of thecommercial PCT immunoassays available for sepsis diagnosis, while—aswill be explained below—the isolated attempts to date with regard to aPCT determination in CSF by the known assays led to contradictoryresults providing little information, the invention also relates,according to claim 13, very generally to the use of a highly sensitiveimmunoassay for procalcitonin determination having a functional assaysensitivity (FAS) of 50 ng/l or better, in particular of 10 ng/l orbetter, for the determination of procalcitonin immunoreactivity incerebrospinal fluid (CSF).

Functional assay sensitivity (FAS; also functional inter assaysensitivity) is defined as a parameter which indicates the analyteconcentration which is measured by the respective method with aninterassay precision (an interassay coefficient of variation) of ≦20%(35).

The present invention is based on considerations by the inventors forimproving the diagnosis of dementias and in particular the differentialdiagnosis for distinguishing between different forms of preseniledementia by applying the discovery that the known forms of preseniledementia explained in more detail at the outset are also accompanied—todifferent extents—by inflammatory processes which are regarded asessential for the development, the symptoms and the course of dementias.

Thus, Alzheimer's disease is characterized, inter alia, by theoccurrence of chronic local inflammatory reactions in the brain withparticipation of various inflammatory proteins, such as complementfactors, acute-phase proteins and proinflammatory cytokines (1, 30).

Inflammatory processes also play a role in the origin of vasculardementias (VAD). The levels of TNFα, TGFβ, IL-6 and GM-CSF(granulocyte-macrophage colony-stimulating factor) are substantiallyelevated in patients with VAD (28; 29).

It is presumed that both in the case of AD and in the case of VAD asimilar cytokine production cascade is started as a response to neuronaldamage, although the triggering factors of these two forms ofneurodegeneration are different and lead to different neuropathologicalchanges in the brain (28).

In DLB, too, inflammatory processes appear to play a role. Thus, thenumber of activated microglia cells in the brain of patients with DLB isincreased (15), and proinflammatory cytokines, such as TNFα, areoverexpressed in certain regions of the brain, such as the amygdala andthe hippocampus (13).

There are only sparse indications for the occurrence of inflammatoryreactions in the brain of FTD patients. In a study by Sjogren et al., itwas possible to measure significantly elevated concentrations of thepro-inflammatory cytokine TNFα and of the anti-inflammatory cytokineTGFβ in the cerebrospinal fluid of some FTD patients (26).

Against a background of extensive clinical material and extensiveexperience on the part of the Applicant which relates to the occurrenceof the peptide procalcitonin (PCT) in the serum and plasma of sepsispatients and other patients, the inventors thought it a worthwhileproblem to determine whether changes of PCT concentrations which can berelated in a diagnostically relevant manner to dementias and otherneuroinflammatory diseases can be determined in the CSF.

Procalcitonin (PCT) is a peptide which consists of 116 amino acids andwas first discussed as a precursor of the important hormone calcitonin(thyreocalcitonin) and the complete amino acid sequence of which hasbeen known just as long as the details of its proteolytic degradationwhich leads to the liberation of the mature hormone calcitonin and othershorter peptides, including in particular so-called katacalcin(procalcitonin 96-116) and an n-terminal peptide (n-procalcitonin 1-57),which are abbreviated herein to “PCT partial peptides”. As explained inmore detail, for example, in the patents EP 0 656 121 B1 and U.S. Pat.No. 5,639,617 and in (2), severe bacterial inflammations with systemicreaction result in the release of PCT into the circulation where it isfound in very high, readily measurable amounts (2; cf. also theoverviews in 22; 33; 3). Reference is made expressly to the generaltechnical knowledge recorded in said patents and references forsupplementing the present description. Viral, autoimmune and allergicdiseases on the other hand do not lead to a significant increase in thePCT concentration in the blood. PCT reflects the severity of a bacterialinfection and is used as a marker for the diagnosis and therapeuticmonitoring of sepsis, severe sepsis and septic shock (5; 7; 27; 32; 21).

The determination of PCT may also be used for differential diagnosticpurposes since inflammatory diseases of infectious aetiology can bedistinguished from those of non-infectious aetiology on the basis of themeasurable PCT concentrations in serum and plasma (cf. also EP 0 880 702B1).

PCT is determined, as described in the abovementioned patents andreferences, in a suitable manner by immunoassays of the sandwich typeusing two antibodies which bind to the amino acid sequence of thecomplete PCT peptide so that the PCT processed completely with releaseof calcitonin is not detected but the total unprocessed PCT andoptionally also those longer PCT partial peptides which have bothbinding sites for the antibodies used in the assay are detected. Sincethe sandwich assays used do not as such detect exclusively the completeunprocessed PCT, it is preferred in the present application to refer tothe determination of a PCT immunoreactivity instead of a PCTdetermination, with the result that the appearance of a stipulation foran exclusive measurement of a molecule with the complete PCT sequence isto be avoided. In general, the measurement of the PCT immunoreactivitycan be designated as a measurement by a sandwich immunoassay using twoantibodies which bind to those segments of the complete PCT peptidewhich, in the proteolytic processing of PCT with formation ofcalcitonin, are located on different members of the PCT partial peptidesformed or which are located on PCT partial peptides which do notcomprise the calcitonin sequence.

The fact that it is not the complete PCT 1-116 which is determined inserum or plasma in the case of sepsis but a PCT 3-116 shortened by twoamino acids is explained in EP 1 121 600 A1 and EP 1 48 334 A1 or U.S.Pat. No. 6,756,483, which are referred to for supplementing the presentdescription.

For the determination of the procalcitonin immunoreactivities inserum/plasma, there exists, for example, the commercialchemiluminescence assay LUMItest® PCT (B.R.A.H.M.S. AG), which has afunctional assay sensitivity (FAS) of 300 ng/l and is tailored to PCTdetermination in sepsis, where very high PCT concentrations can occur.For PCT determination with a higher sensitivity, a modified sandwichimmunoassay which operates with an affinity-purified polyclonal antibodyand which is described in more detail in (20) and is obtainable asLUMItest® PCTsensitiv (B.R.A.H.M.S AG) was recently developed. Thisassay has a clearly better FAS of 7 ng/l (20). With the aid of thisassay, it was possible to determine a mean PCT serum concentration of13.5 ng/l (13.5 pg/ml) in healthy persons, values from <7 to 63 ng/lhaving been found and the 97.5% percentile being 42.5 ng/l.

Data on experiments to measure PCT in CSF too, appear only sparsely inthe scientific literature, and all measurements described were carriedout under premises which cannot be logically related to thedetermination, according to the invention, of PCT in CSF for thediagnosis of dementias and further neuroinflammatory diseases:

Starting from the suitability of PCT as an infection marker, an attemptwas made to determine whether PCT concentrations in the CSF of patientswith meningitis (8; 12; 25) or Lyme borreliosis (14) are measurable andmay permit a distinction between bacterial meningitis and viralmeningitis. The findings were contradictory, either no increasedmeasured values at all being obtained (8; 25) or only a weak indicationbeing possible (12).

Starting from a genetic relationship between PCT and the peptide CGRP(calcitonin gene related peptide) and homologous sequence designationsfor adrenomedullin (ADM), which was measured at elevated levels in theCSF of children with traumatic brain injury (TBI), it was furthermoreinvestigated whether elevated PCT concentrations can be found in the CSFin the case of such children too (10). There, it was possible to findelevated PCT concentrations, which were related to an acute-phasereaction to the trauma, even if the significance of the observations asa whole remained unclear. It is not possible to find any recognizablelogical relationship with measurements in the case of dementias andfurther neuroinflammatory diseases which form the subject of the presentinvention.

In all cases where an attempt was made to determine PCT in the CSF, thecommercial assay developed for sepsis diagnosis in serum or plasma,which had an FAS of only 300 ng/l, was employed.

The Applicants have reason to assume that considerably improved measuredresults with better diagnostic significance are obtained in the CSF alsoin the case of, for example, infectious diseases, such as bacterialmeningitis, if measurements as described, for example, in (8; 12) arecarried out by a highly sensitive PCT assay according to (20), as wasused in the case of the measurements which form the basis of the presentinvention and are described in the experimental section. It should bepointed out that clear standard concentrations for healthy persons couldbe determined by such a highly sensitive assay under the conditionsdescribed. The present application therefore furthermore relates verygenerally to the measurement of PCT in the CSF by a highly sensitiveimmunoassay for diagnostic purposes.

Below, the invention is explained in more detail with reference tomeasured results and a figure.

FIG. 1 shows the results of the measurement of the PCT immunoreactivityin the CSF of healthy normal persons (HC) and in the CSF of patientswith four different diagnosed types of presenile dementias, namelyfrontotemporal dementia (FTD), Alzheimer's dementia (pAD), vasculardementia (VAD) and dementia with Lewy bodies (DLB), and with the medianconcentrations and sensitivities for the individual forms of dementiafor the measured groups of patients.

EXPERIMENTAL SECTION Description of Assay

The measurement of procalcitonin in the cerebrospinal fluid was effectedas described in (20). However, the lyophilised standards were dissolvednot in zero serum but in PBS (with 1% BSA).

Measurement of the PCT Immunoreactivity in the Cerebrospinal Fluid ofHealthy Controls and Patients with Presenile Dementias

Procalcitonin was detected with the LUMItest® PCTsensitiv (cf. 20) incerebrospinal fluid of healthy control persons. It was possible to showthat the concentrations are in the range between 12 and 133 ng/l (medianconcentration 50 ng/l). Since the median PCT concentration in the serumof healthy persons was determined only as 13.5 ng/l (20), there is a PCTconcentration gradient between blood and CSF of about 1:4 in healthypersons.

The measured PCT concentrations in the cerebrospinal fluid of healthycontrols and patients with different forms of presenile dementia areshown in FIG. 1.

The respective sensitivity and specificity of the highly sensitiveLUMItest® PCTsensitiv assay for the diagnosis of different preseniledementias are shown in table 1.

TABLE 1 Specificity and sensitivity of the measurements of the PCTimmunoreactivity in the CSF of patients with different dementiasDementia Specificity (%) Sensitivity (%) Subjective cognitive 100 50disturbances Frontotemporal dementia 100 25 Alzheimer's dementia* 100 60Vascular dementia 100 59 Dementia with Lewy bodies 100 75Group of patients diagnosed with “probable Alzheimer's disease” (pAD),the diagnosing institution having a mean statistical reliability forAlzheimer diagnosis of 90%.

According to FIG. 1, the measured results show different medianconcentrations for the different patient groups, the group of FTDpatients (patients with subjective cognitive disturbances) giving onaverage only slightly higher measured values than healthy persons anddiffering substantially from the other patient groups in whom the meanPCT concentrations (i) were considerably elevated compared with healthypersons, and (ii) also differed from group to group. DLB patients hadthe highest measurable PCT concentrations and were found to be positivewith a high sensitivity of 75% (within the clinically presorted groups;specificity 100%).

LITERATURE

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1. A CSF diagnostic in vitro method for detection, determination ofseverity and monitoring and prognosis of dementias and neuroinflammatorydiseases, wherein a determination of the procalcitonin immunoreactivity(PCT immunoreactivity) is carried out in a sample of the cerebrospinalfluid (CSF) of a patient who is suffering from a dementia orneuroinflammatory disease or is suspected of suffering from such adisease, and conclusions about the presence, the course, the severity orthe success of a treatment of the dementia or neuroinflammatory diseaseare drawn from a measured PCT immunoreactivity which is above athreshold value typical for healthy control persons.
 2. The methodaccording to claim 1, wherein the PCT immunoreactivity is determinedwith the aid of a highly sensitive PCT immunoassay having a functionalassay sensitivity (FAS) of better than 100 ng of PCT per 1 (100 ng/l or100 pg/ml), preferably better than 10 ng/l.
 3. The method according toclaim 1, wherein an average value which is determined for healthycontrol persons and is about 50 pg/ml is used as a threshold value forthe diagnosis “suspicion of neuroinflammatory disease”.
 4. The methodaccording to claim 1, wherein the PCT immunoassay for measurement of thePCT immunoreactivity is a sandwich immunoassay using two antibodieswhich bind to those segments of the complete PCT peptide which arelocated on different members of the PCT partial peptides formed in theproteolytic processing of PCT with formation of calcitonin or which arelocated on PCT partial peptides which do not comprise the calcitoninsequence.
 5. The method according to claim 4, wherein one of theantibodies binds to a segment of the calcitonin sequence and the otherof the antibodies binds to a segment of the katacalcin sequence, and inthat at least one of the two antibodies is an affinity-purifiedpolyclonal antibody.
 6. The method according to claim 1, wherein thedementia is a presenile dementia selected from the group consisting ofAlzheimer's dementia (AD), dementia with Lewy bodies (DLB),frontotemporal dementia (FTD) and various forms of vascular dementia(VAD), and in that the method is carried out as part of differentialdiagnosis.
 7. The method according to claim 6, wherein the method iscarried out as a differential diagnostic method in which the measuredPCT immunoreactivity values are related to value ranges typical for theindividual forms of dementia and a probability of the presence of one ofthe possible forms of dementia is determined.
 8. The method according toclaim 1, wherein the neuroinflammatory disease is a chronicneuroinflammatory disease of non-infectious aetiology.
 9. The methodaccording to claim 1, wherein said method is carried out as part of amulti-parameter determination in which at least one further biochemicalor physiological parameter informative for the respective clinicalpicture is simultaneously determined and in which the measured result isobtained in the form of a set of at least two measured variables whichis evaluated for the fine diagnosis of dementia or neuroinflammatorydisease.
 10. The method according to claim 9, wherein, as part of themulti-parameter determination, in addition to the PCT immunoreactivity,at least one further inflammation mediator is determined which isselected from the group consisting of complement components, cytokines,chemokines, blood coagulants and fibrinolytic factors, acute-phaseproteins and free radical compounds.
 11. The method according to claim9, wherein the multi-parameter determination is carried out as asimultaneous determination by means of a chip technology measuringapparatus or an immunochromatographic measuring apparatus.
 12. Themethod according to claim 9, wherein the evaluation of the complexmeasured result of the multi-parameter determination is effected withthe aid of a computer program.
 13. (canceled)